The combination of cocaine with alcohol is one of the most frequent patterns of combined drug use. Morbidity and mortality from cocaine appears to be exacerbated by the concomitant use of alcohol. Epidemiological studies have shown that the combined use of cocaine and alcohol results in an eighteen-fold increase in the risk of sudden death (Rose et al 1991). Although the mechanisms by which this interaction increases cocaine toxicity are not understood, there is recent evidence that they could result from the production of cocaethylene (the ethyl homologue of cocaine), a cocaine metabolite probably resulting from the transesterification of cocaine and ethanol in the liver (Hearn et al, 1991). Cocaethylene cocaine abusers who presumably die due to toxicity from the concomitant use of cocaine and alcohol. Cocaethylene has been shown to be pharmacologically active and is equipotent to cocaine as an inhibitor of the dopamine transporter in vitro. The purpose of this project is to use positron emission tomography and [11C]cocaethylene to investigate the rate of uptake, the regional distribution and the binding characteristics of cocaethylene in the brain in vivo as it compares to cocaine. We will also use PET to measure the effects of acute cocaine and cocaethylene on changes in synaptic dopamine concentration. These measurements will enable us to assess whether cocaethylene is as pharmacologically active as cocaine at the dopamine transporter in vivo. If cocaethylene proves to be as active as cocaine at the dopamine transporter, the combined action of cocaine and this metabolite could enhance the reinforcing properties of cocaine. Moreover, if the examination of the pharmacokinetics and metabolic stability of cocaethylene reveal that a considerable amount of this substance is available for uptake into the brain, this will be important relative to understanding the potential contribution of this metabolite to toxicity from combined alcohol/cocaine use. We are hypothesizing that cocaethylene clearance from the tissue and plasma will be slower and the absolute brain uptake will be higher than that of cocaine and that this may in part explain the increased toxicity associated with the combined use of cocaine and alcohol. We also hypothesize that the actions of cocaethylene on the dopamine transporter act as a positive reinforcement that promotes the combined use of alcohol and cocaine.